Interleukin-1 and Systemic Sclerosis: Getting to the Heart of Cardiac Involvement

Abstract

Systemic sclerosis (SSc) is rare, severe connective tissue disease characterized by endothelial and vascular damage, immune activation, and resulting in inflammation and fibrosis of skin and internal organs, including the heart. SSc is associated with high morbidity and mortality. Cardiac involvement is frequent in SSc patients, even though often asymptomatic at early stages, and represents one of the major causes of SSc-related mortality. Heart involvement has a variable clinical presentation, and its pathogenesis is not completely understood. Myocardial fibrosis is traditionally considered the immunopathologic hallmark of heart involvement in SSc. This unique histological feature is paralleled by distinctive clinical and prognostic features. The so-called "vascular hypothesis" represents the most credited hypothesis to explain myocardial fibrosis. More recently, the prominent role of an inflammatory myocardial process has been identified as a cardinal event in the evolution to fibrosis, thus also delineating an "inflammation-driven pathway to fibrosis". The pro-inflammatory cytokine interleukin (IL)-1 has an apical and cardinal role in the myocardial inflammatory cascade and in cardiac dysfunction. The primary aim of this perspective article is: to present the emerging evidence on the role of IL-1 and inflammasome in both SSc and heart inflammation, to review the complex interplay between cellular metabolism and inflammasome activation, and to discuss the rationale for targeted inhibition of IL-1 for the treatment of SSc-heart involvement, providing preliminary experimental and clinical data to support this hypothesis.

Keywords: cellular metabolism; heart inflammation; inflammasome; interleukin-1; systemic sclerosis (scleroderma).

Figure 1

Inflammasome and metabolism in systemic sclerosis. Molecular pathways involved in the metabolic regulation of the NLRP3 inflammasome in SSc: TCA cycle, fatty acid imbalance, and amino-acid metabolism. In SSc, a complex biological loop in which the TGF-β1 rich microenvironment, the upregulated glutamine metabolism, and the fatty acid dysregulation, could lead to both inflammasome activation with IL-1β release and myofibroblasts differentiation, thus foraging the inflammation-driven fibrosis. Succinate is formed in the TCA cycle; its levels increase the TGF-β1-induced HIF-1α expression, promoting fibroblast differentiation. High levels of succinate can support IL-1β expression by stabilizing HIF-1α for IL-1β transcript expression to occur. This process is inhibited by itaconate. TGF‐β1 itself is able to enhance succinate production, thus foraging this biological loop. SSc fibroblasts have an increased glutaminase expression, and an altered glutamine metabolism is an ubiquitous trait in SSc. The glutammate-glutamine pathway activates the NLPR3 inflammasome. Fatty acid metabolism has been implicated in the regulation of NLRP3 inflammasome: metabolic imbalance itself act as a cue to activate an inflammatory response, though the production of mitochondrial reactive oxygen species (mtROS), which directly activate the NLRP3 inflammasome. PUFAs, particularly ω-3 PUFA, regulate NLRP3 inflammasome activation, acting as potent inhibitors of both caspase-1 activation and IL-1β release. Fatty acid metabolism is dysregulated in SSc, and intradermal adipose tissue is atrophied and replaced by collagen-rich fibrous tissue in SSc. SSc, systemic sclerosis; TGF-β1, transforming-growth factor beta-1; HIF-1α, hypoxia-inducible factor-1alpha; TCA, tricarboxylil acid; IL-1β, interleukin-1 beta; PUFAs, long-chain polyunsaturated fatty acids.

Figure 2

Interleukin-1, myocardial inflammation, and heart fibrosis in systemic sclerosis. Heart inflammation results in myocardial injury. As a consequence, IL-1α is released from dying myocardiocytes, together with intracellular debris and inflammatory mediators; these in turn activate a molecular complex known as the “inflammasome” inside macrophages which processes and releases active IL-1β. Once induced, inflammation escalates into a redundant process: hence, other pro-inflammatory cytokines, mainly IL-6, are produced and they perpetuate heart inflammation and inflammation-driven fibrosis. IL-1 and IL-6 also promote Th17 differentiation, and in post-myocarditis, the role of IL-17A emerged in myocardiac remodeling, thus contributing to both myocardial fibrosis and progression to dilated cardiomyopathy. Finally, in SSc fibroblasts, the NLRP3 inflammasome is over-expressed with consequent increased production of IL-1b. IL-1 also stimulate SSc fibroblasts and induce the synthesis of micro-RNA (miR)-155 which establishes an autocrine loop further increasing IL-1 signaling.